When a biological organism is exposed to a foreign substance as an antigen, an IgE antibody specific to the antigen is produced in the body, and when the same antigen invades again, binding of IgE antibody with the IgE receptor formed on the surface of mast cells (also called mastocytes) stimulates extracellular release of the chemical mediators contained in granules in the mast cells, such as histamine, serotonin, platelet activating factor (PAF), heparin and the like. As a result, promotion of capillary permeability, bronchial smooth muscle constriction, increase in the secretion due to exocrine gland stimulation and the like are induced, which in turn leads to the onset of allergic inflammations such as anaphylactic shock, bronchial asthma, allergic rhinitis, hives, atopic dermatitis, drug hypersensitivity and the like.
Mast cells are responsible for not only the onset of allergic conditions caused by various chemical mediators released by stimulation of antigen and the like but also chronic allergic inflammation caused by the release of cytokines secondarily produced in the mast cells (M. K. Church & J. P. Caulfield, Chapter 5, pp. 5.1–5.12, Allergy, ed. S. T. Holgate et al., Gower Medical Publishing, London, UK (1993)).
Furthermore, the release of chemical mediators from the mast cells is induced not only by the action via IgE receptors but by various substances (IgG, complement, neuro-peptide, calcium ionophore, phorbol ester etc.). While the phenomenon of extracellular release of chemical mediators from the mast cells (degranulation) is considered to involve various factors such as cyclic AMP (cAMP), calcium ion, sodium ion, phosphoinositide metabolism, protein kinase C, phospholipase A2, changes in membrane potential, and the like, but the detail thereof has not been elucidated (D. A. Kennerly & P. A. Duffy, Chapter 4, pp. 4.1–4.14, Allergy, ed, S. T. Holgate et al., Gower Medical Publishing, London, UK, (1993)).
As the therapeutic agent (hereinafter to be referred to as antiallergic agent) for allergic inflammations induced by these chemical mediators, either a pharmaceutical agent that suppresses the action of chemical mediators released from the mast cells, or a pharmaceutical agent that suppresses degranulation of the mast cells is currently used.
Adrenocorticosteroid drugs, which are typical antiallergic agents that suppress the action of chemical mediators, are effective but, due to the side effect associated with long-term administration, the development of a nonsteroidal antiallergic agent has been desired.
As nonsteroidal antiallergic agents, antihistamic agents, anti-leukotriene agents, anti-PAF agents, thromboxane A2 synthase inhibitors and antagonists and the like are commercially available or under development, that block the action of chemical mediators released from mast cells, basophil and the like, activated by IgE antibody.
However, it is extremely difficult to create a pharmaceutical agent that basically suppresses degranulation of the mast cells. This is because the process of release of chemical mediators by mast cells stimulated by IgE antibody is extremely complicated and the mechanism of degranulation has not been clearly elucidated, as mentioned above. At present, pharmaceutical agents considered to have a degranulation suppressive action have been approved as antiallergic pharmaceutical products free of anti-histamic action and used for clinical treatment. Under the present situation, however, their action mechanisms are indefinite and the degranulation suppressive action is too weak to afford a superior treatment effect.
It is therefore an object of the present invention to provide a novel means for developing a pharmaceutical agent capable of basically suppressing the degranulation of the mast cells, and to provide a novel antiallergic agent that suppresses degranulation using this means.